Engineered cancer cells can fight primary and metastatic cancer

What if cancer cells could be re-engineered to turn against their own kind? A new study led by researchers at Brigham and Women’s Hospital leverages the power of gene editing to take a critical step toward using cancer cells to kill cancer. The team reports promising results in preclinical models across multiple types of cancer cells, establishing a potential roadmap toward clinical translation for treating primary, recurrent and metastatic cancer. Results are published in Science Translational Medicine.

“This is just the tip of the iceberg,” said corresponding author Khalid Shah MS, Ph.D., director of the Center for Stem Cell Therapeutics and Imaging (CSTI) in the BWH Department of Neurosurgery and faculty at Harvard Medical School and Harvard Stem Cell Institute (HSCI). “Cell-based therapies hold tremendous promise for delivering therapeutic agents to tumors and may provide treatment options where standard therapy has failed. With our technique, we show it is possible to reverse-engineer a patient’s own cancer cells and use them to treat cancer. We think this has many implications and could be applicable across all cancer cell types.”

The new approach capitalizes on cancer cells‘ self-homing ability—the process in which cancer cells can track the cells of their kind that have spread within the same organ or to other parts of the body. Harnessing this power could overcome drug delivery challenges, helping get therapeutics to tumor sites that may otherwise be difficult to reach.

The team developed and tested two techniques to harness the power of cancer cells. The “off the shelf” technique used pre-engineered tumor cells that would need to be matched to a patient’s HLA phenotype (essentially, a person’s immune fingerprint). The “autologous” approach used CRISPR technology to edit the genome of a patient’s cancer cells and insert therapeutic molecules. These cells could then be transferred back into the patient.

The CRISPR-engineered cancer cells (green) migrated towards an established glioblastoma tumor site (red) over the course of 28 days in a mouse model. Credit: C. Reinshagen et al., Science Translational Medicine (2018)

To test both approaches, the team used mouse models of primary and recurrent brain cancer and breast cancer that has spread to the brain. The team saw direct migration of engineered cells to the sites of tumors and found evidence that the engineered cells specifically targeted and killed recurrent and metastatic cancer in the mice. The researchers report that the treatment increased the survival of the mice. Engineered cells were equipped with a “kill switch” that could be activated after treatment—PET imaging showed that this kill switch worked to eliminate the cells.

“Our study demonstrates the therapeutic potential of using engineered tumor cells and their self-homing properties for developing receptor-targeted therapeutics for various cancers,” said Shah.

 Explore further: How targeting metabolism can defeat cancer stem cells

More information: C. Reinshagen el al., “CRISPR-enhanced engineering of therapy-sensitive cancer cells for self-targeting of primary and metastatic tumors,” Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aao3240

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Hep C vaccine could dramatically reduce transmission in people who inject drugs

Among the most serious consequences of the opioid epidemic is the spread of hepatitis C among injecting drug users.

A major new study shows that if a hepatitis C vaccine were successfully developed, it would dramatically reduce transmission of hepatitis C among drug users—even though it’s unlikely such a vaccine would provide complete immunity.

The study, which employed mathematical modeling, is published in Science Translational Medicine.

Four of the study’s authors are members of the Program for Experimental and Theoretical Modeling in the division of hepatology of Loyola Medicine and Loyola University Chicago Stritch School of Medicine. One of the Loyola researchers, Harel Dahari, Ph.D., is a co-senior author of the study, along with Marian Major, Ph.D., of the U.S. Food and Drug Administration. Dr. Dahari is an assistant professor at Loyola University Chicago Stritch School of Medicine.

Vaccines are currently available for hepatitis A and hepatitis B, but a vaccine for hepatitis C is still under investigation. A clinical trial is testing an experimental hepatitis C vaccine on injecting drug users. Unlike many other vaccines, the hepatitis C vaccine is not expected to provide complete immunity, known as sterilizing immunity. A vaccinated person exposed to HCV could still be infected with the virus, although the amount of virus in the bloodstream would be significantly reduced.

The new study calculated how effective a vaccine that provided incomplete immunity would be in preventing transmission among injecting drug users. Researchers developed a mathematical model to determine transmission probabilities in drug users who share needles and syringes. They simulated the sharing of two types of common syringes used by drug users. Using previously published data from people infected or reinfected with hepatitis C virus, researchers then estimated the transmission risks between injecting drug users.

Illustration of hepatitis C transmission via a shared syringe showing how the virus-contaminated blood (red) mixes with the drug (blue) while being injected by an infected individual (A-B). A small amount of the infected mixture remains …more

The study estimated that if an injecting drug user shared a syringe/needle with a second drug user who was infected with hepatitis C, there would be a greater than 90 percent chance the first drug user would also become infected with hepatitis C after six months. However, if a vaccine were used, the transmission risk would decrease to between 1 and 25 percent, depending on the type of needle used and other factors.

“Our findings suggest that a hepatitis C vaccine would be an essential part of a comprehensive prevention strategy to meet the World Health Organization’s goal of eradicating hepatitis C by 2030,” said study co-author Scott Cotler, MD, head of Loyola’s division of hepatology and a professor in the department of medicine of Loyola University Chicago Stritch School of Medicine. Other Loyola co-authors are mathematical modelers Alexander (Sasha) Gutfraind, Ph.D., and Louis Shekhtman, MSc.

Hepatitis C is caused by the hepatitis C virus (HCV). Long-term infection with HCV, known as chronic hepatitis C, usually is silent for many years. But the disease eventually can cause cirrhosis (advanced scarring) of the liver, liver cancer and liver failure. In the United States, as many as 3 million people are chronically infected with HCV, with more than 30,000 new infections per year.

Hepatitis C spreads through contaminated blood, and an estimated 60 percent of HCV infections in the U.S. are attributed to sharing needles, syringes or other drug paraphernalia.

Antiviral drugs are used to treat hepatitis C, with cure rates higher than 90 percent. In addition to stopping the disease from progressing, antivirals also can prevent transmission. However, antivirals are expensive, and many injecting drug users lack access to healthcare in the U.S. And even if they are cured, injecting drug users can become infected again if they continue to share needles.

“While extremely effective, antivirals alone are unlikely to eliminate hepatitis C globally,” Dr. Dahari said. “We need to combine antivirals with a hepatitis C vaccine and harm-reduction measures such as needle-syringe exchange programs, opioid substitution therapy and behavioral counseling.”

Some people think a vaccine needs to be perfect, Dr. Dahari added. “But we found that a vaccine still can be extremely beneficial even if it does not provide complete sterilizing immunity.”

More information: M. Major el al., “Modeling of patient virus titers suggests that availability of a vaccine could reduce hepatitis C virus transmission among injecting drug users,” Science Translational Medicine (2018). stm.sciencemag.org/lookup/doi/ … scitranslmed.aao4496

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Soccer headers may be linked to balance problems

Soccer players who head the ball more often may be more likely to have balance problems than players who do not head the ball as often, according to a preliminary study released today that will be presented at the American Academy of Neurology’s Sports Concussion Conference in Indianapolis July 20 to 22, 2018.

“Soccer headers are repetitive subconcussive head impacts that may be associated with problems with thinking and memory skills and structural changes in the white matter of the brain,” said study author John Jeka, Ph.D., of the University of Delaware in Newark, Del. “But the effect of headers on balance control has not been studied.”

For the study, 20 soccer players recruited from the community in Newark took a balance test where they walked along a foam walkway with their eyes closed under two conditions: with galvanic vestibular stimulation (GVS) and without GVS. For GVS, electrodes placed behind each ear stimulate the nerves that send messages from the balance system in the inner ear to the brain. So the stimulator can make you feel like you are moving when you are not. In this case, it made participants feel like they were falling sideways.

The soccer players, who had an average age of 22, also completed questionnaires about how many times they had headed the ball during the past year. The number of headers over a year for each participant ranged from 16 to 2,100, with an average of 451 headers. Those numbers were calculated by asking participants for the average number of headers during a practice and game, the average number of practices and games per week, and the average number of months per year that the player participated.

The study found that the players with the largest number of headers had the largest balance responses to GVS in both foot placement and hip adduction during the walking test, which indicated that they had vestibular processing and balance recovery problems. Researchers found for every 500 headers, foot placement response increased about 9 millimeters and hip adduction response increased about 0.2 degrees.

“Soccer players must have good balance to play the game well, yet our research suggests that headers may be undermining balance, which is key to all movement, and yet another problem now linked to headers,” said study author Fernando V. Santos, PT, of the University of Delaware. “It is important that additional research be done to look more closely at this possible link with balance and to confirm our findings in larger groups of people.”

A limitation of the study was that participants relied on memory when reporting how many times they headed the ball.

 Explore further: Heading—not collisions—cognitively impairs players

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Late-life high blood pressure may harm the brain

Decades ago, hundreds of nuns and priests made an extraordinary decision: They agreed to donate their brains upon death to science, hoping to help solve mysteries about Alzheimer’s and other diseases. Now, a study that used their gifts is giving some clues. It reveals that high blood pressure late in life might harm the brain.

Autopsies on nearly 1,300 older people, including about 640 clergy members, found more signs of damage and one of the hallmarks of Alzheimer’s disease in the brains of those with higher blood pressure than among those with pressure closer to normal, researchers reported Wednesday.

The study does not prove cause and effect, and it does not yet provide a comparison of rates of dementia or its most common form, Alzheimer’s—those results will take longer to parse. But it challenges a theory that high pressure is not as harmful in old age as it is when people are younger.

“We can’t be alarmist. This is preliminary data” that needs to be validated by others, said the study leader, Dr. Zoe Arvanitakis of Rush University Medical Center in Chicago. “It’s far too soon to make recommendations about blood pressure in older people based on this study.”

The research began in 1994 and combined people from three studies of aging who agreed to donate their brains for autopsy upon their death, including the Religious Orders Study of Catholic clergy throughout the United States. All were over 65 and without known dementia at the start and were followed until they died—at an average age of 89 and after an average of eight years in the study.

Two-thirds had high blood pressure, defined as a top reading of 140 or more when the study began (it’s now 130 under new guidelines adopted last fall.) Their pressures were measured once a year during the study—a strength of this work over some previous research that just relied on people to say whether they had high pressure or not.

After each participant died, researchers examined their brains for areas of dead tissue caused by lack of blood supply. These blighted areas can be tiny and cause no symptoms, so they’re sometimes called evidence of “silent strokes.”

About half of the study participants had one or more of these, and the risk was greater for those with higher blood pressure. For example, people with an average top reading of 147 had a 46 percent greater risk of having one or more of the bad spots than those with an average top reading of 134. People with higher bottom blood pressure readings also had a greater risk for this problem.

Researchers also found a link between higher pressure and one of the signs of Alzheimer’s—tangles of a protein called tau—but not another Alzheimer’s hallmark, amyloid plaques. This needs further research to understand the implications, Arvanitakis said.

“It’s a pretty strong study,” said James Hendrix, director of global science initiatives at the Alzheimer’s Association. “Autopsy data is really powerful” and has been the gold standard for diagnosing Alzheimer’s for many years, he said.

With Alzheimer’s, changes in the brain occur a decade or more before symptoms do, so high blood pressure may have been doing damage well before the age when these people enrolled in the study, he said.

How might high pressure do harm?

“Lower blood pressure reduces the risk of those blood vessel blockages” that can cause a silent stroke, said another independent expert, the Mayo Clinic’s Dr. David Knopman. The work shows that “treating blood pressure throughout the lifespan is important.”

Knopman is a spokesman for the American Academy of Neurology, whose journal, Neurology, published the study. Federal grants paid for the work.

 Explore further: Higher blood pressure may be linked to brain disease, Alzheimer’s

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Dog illness can spread to owners

A bacteria carried by dogs that haven’t been neutered can produce flu symptoms in humans and potentially jeopardize a pregnancy, a new study suggests.

Brucellosis infection is most commonly spread by livestock like sheep, cattle, goats and pigs.

But a strain of the bacterium carried by dogs — Brucella canis — could be widespread in humans, warned lead researcher Martha Hensel, a veterinarian with Texas A&M University.

“We don’t really know how prevalent this disease is in the United States,” Hensel said. “The information we have to draw conclusions on the public health risk is outdated, to say the least — something like 30 to 40 years old.”

B. canis is carried by dogs that can still reproduce, Hensel noted. It’s not clear exactly how the bacteria might spread to humans, but it’s most likely passed through contact with reproductive organs or urine.

People who regularly handle such dogs — vets, dog shelter employees, dog breeders — are most at risk for contracting brucellosis, Hensel said.

However, pet ownership is a likely risk factor for infection, particularly for young children and people with compromised immune systems, Hensel and her colleagues explained.

The researchers highlighted some case studies:

• A 3-year-old New York City girl came down with brucellosis in 2012 after exposure to an infected puppy recently purchased from a pet store.
• Several people with HIV have developed brucellosis in recent years, all linked to intact dogs they owned that were later diagnosed with B. canis infection.

“An average, healthy adult would probably not contract this disease unless they were exposed to a really high concentration of bacteria,” Hensel said.

Brucellosis primarily causes symptoms similar to the flu — fever, sweats, fatigue, headache and muscle pain, according to the U.S. Centers for Disease Control and Prevention.

The disease also can cause long-term or recurring symptoms, such as arthritis, swelling of the testicles, swelling of the heart, neurologic symptoms and chronic fatigue, the agency noted.

Brucellosis can also mean trouble for a pregnancy, said Dr. Amesh Adalja, a senior scholar with the Johns Hopkins Center for Health Security.

“Though brucellosis is a common cause of animal [miscarriages], it is also linked to fetal problems in women who are pregnant when they contract it — though at a lesser degree than with other animal species,” Adalja explained. “The diminished role is due to the lack of a specific compound produced in human placenta [erythritol] as well as anti-brucella activity in human amniotic fluid.”

The CDC recommends that pregnant women talk with their doctor if they’ve been exposed to brucellosis, saying that a short course of antibiotics could be “lifesaving for the fetus.”

Hensel and her colleagues suggested that better diagnostic tools should be developed to help determine the prevalence of B. canis in both dogs and humans.

“At this point, we don’t know what the incidence in the United States is, and how many dogs are carrying this bacteria,” Hensel said. “We would like to put that out there for clinicians to think about, in terms of the risk of transmission from dogs to people.”

The new study was published online July 11 in the journal Emerging Infectious Diseases.

More information

The U.S. Centers for Disease Control and Prevention has more about brucellosis.

SOURCES: Martha Hensel, DVM, Texas A&M University, College Station, Texas; Amesh Adalja, M.D., senior scholar, Johns Hopkins Center for Health Security, Baltimore; July 11, 2018, Emerging Infectious Diseases, online

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3 of 4 Black Americans have high blood pressure by age 55

A startling 75 percent of black people in the United States develop high blood pressure by the age of 55, a new study finds.

That’s a far higher rate than seen among either white men (55 percent) or white women (40 percent), the researchers said.

“We started to see differences between blacks and whites by age 30,” said lead researcher S. Justin Thomas.

“We need to start focusing on preventing hypertension [high blood pressure], particularly in blacks, at an early age,” he added.

Thomas is an assistant professor at the University of Alabama at Birmingham’s department of psychiatry.

It isn’t known why black Americans are more prone to high blood pressure at an earlier age than white Americans, Thomas said. But he speculated that a combination of lifestyle and genetics may explain why.

Thomas said preventing high blood pressure needs to start with getting kids to develop healthy habits.

“I don’t think you can start too early,” he said. “It should start at elementary school. If kids are told frequently that this is important, they will adopt it.”

High blood pressure can lead to serious health problems over time, the researchers noted.

Dr. Gregg Fonarow explained that high blood pressure “is a leading risk factor for heart attack, heart failure, stroke, kidney disease and premature cardiovascular death.” He is a professor of cardiology at the University of California, Los Angeles, and was not involved with the new study.

Black men and women in the study had twice the risk of high blood pressure than white men and women, even after adjusting for other differences, he added.

“Prevention, awareness, treatment and control of high blood pressure is essential, as cardiovascular disease remains the leading cause of fatal and non-fatal cardiovascular events, disability, hospitalizations and financial hardship,” Fonarow explained.

For the study, Thomas and his colleagues collected data on nearly 3,900 young adults who were part of a heart disease risk study.

The participants were enrolled in the study when they were 18 to 30 years old, and they didn’t have high blood pressure at the time.

High blood pressure is defined as a systolic pressure (the upper number) of 130 mm Hg or higher and a diastolic pressure (the lower number) of 80 mm Hg or higher.

These blood pressure benchmarks were first released in 2017, replacing the previous definition of high blood pressure of 140/90 mm Hg.

This lower threshold for defining high blood pressure means even more Americans will be diagnosed with high blood pressure at younger ages, Thomas said.

Excess weight was the biggest risk factor for developing high blood pressure, regardless of sex or race, the researchers found.

Blacks and whites who kept to a DASH (Dietary Approaches to Stop Hypertension) diet were able to lower their risk for high blood pressure, the study findings showed.

The DASH diet is rich in fruits, vegetables, whole grains, low-fat or fat-free dairy, fish, poultry, beans, seeds and nuts, and low in red meat and salt.

Dr. Byron Lee is director of electrophysiology laboratories and clinics at the University of California, San Francisco. He said that “in many ways, 55 is the new 65. We used to not worry about hypertension until we reached our mid-60s, but it’s clear now that many of us need to take action much sooner.”

Lee pointed out that high blood pressure is a “modifiable risk factor for heart attack and stroke. And if we don’t act on it, we are missing a major opportunity to decrease mortality.”

The report was published online July 11 in the Journal of the American Heart Association.

More information

For more on the DASH diet, visit the American Heart Association.

SOURCES: S. Justin Thomas, Ph.D., assistant professor, department of psychiatry, University of Alabama, Birmingham; Byron Lee, M.D., professor, medicine, director, electrophysiology laboratories and clinics, University of California, San Francisco; Gregg Fonarow, M.D., professor, cardiology, University of California, Los Angeles; July 11, 2018, Journal of the American Heart Association, online

https://bit.ly/2NIIxKz

BioSight Launches Phase 2b Trial of 1st-Line Acute Myeloid Leukemia Treatment

BioSight Ltd., a pharmaceutical development company focused on the development of targeted oncology drugs, announced today that it has received the FDA and the Israeli Ministry of Health clearance to launch a Phase 2b clinical trial of BST-236 for treatment of Acute Myeloid Leukemia (AML).

The trial, which will be launched in the upcoming month, will be conducted in 25 medical centers in the US and Israel. BST-236 will be administered as a single agent treatment for newly-diagnosed AML patients, either de novo or secondary to myelodysplastic disorder (MDS) who are unfit for standard chemotherapy due to its severe toxicity. This population is estimated to account for a third to half of the AML patients.

In the Phase 1/2 study, presented at the Annual American Society of Hematology (ASH) Meeting and Exposition on December 2017, 26 acute leukemia patients were treated with BST-236 as a single agent. The study enrolled mainly older patients with poor prognosis baseline characteristics, including prior treatment with hypomethylating agents for MDS. BST-236 was found to be safe and well tolerated at high doses, with no neurological or gastrointestinal toxicities or renal failure, all of which are life-threatening toxicities associated with the existing chemotherapy and which often attenuate or prevent its use in older patients. This encouraging safety profile allowed the treatment of older and medically unfit patients with high doses of BST-236 and led to 2-3-fold higher response rates compared to currently approved treatments for this patient population. The aim of the Phase 2b study is to repeat the results of the Phase 1/2 study in a larger number of patients in the US and Israel.

Dr. Ruth Ben Yakar, BioSight’s CEO said: “We are excited to launch this Phase 2b clinical trial of BST-236 for treatment of newly-diagnosed AML patients who are unfit for standard chemotherapy. The encouraging results of the Phase 1/2 study suggest that BST-236 may serve as an improved treatment option compared to the approved drugs available today for this population, including for patients at the age of 75 years or more. We think it is very important to approach these patients, mainly due to the general increase in the population’s age and quality of life, and we believe we can provide them with a safer and more effective treatment.”

BST-236 is a novel pro-drug of the chemotherapeutic drug cytarabine. Cytarabine has been the backbone of first-line therapy for AML for the past 40 years, however, it is associated with severe bone marrow, gastrointestinal, and neurological toxicities which significantly limit its use, especially in older and medically unfit patients. BST-236 is designed to enable delivery of high cytarabine doses to leukemia cells with lower systemic exposure to the free drug and relative sparing of normal tissues. As such, BST-236 may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults.

BioSight is a private Israeli clinical-stage pharmaceutical development company, founded by Dr. Stela Gengrinovitch and headed by Dr. Ruth Ben Yakar. BioSight focuses on the development of novel caner-targeted pro-drugs. BioSight’s lead product BST-236 is under clinical development for acute leukemia.

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